A 500-kiloton airburst over Chelyabinsk and an enhanced hazard from small impactors.

Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the atmosphere) have the potential to do greater damage than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave, but owing to lack of observations this is uncertain. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×10(12) joules). We show that a widely referenced technique of estimating airburst damage does not reproduce the observations, and that the mathematical relations based on the effects of nuclear weapons--almost always used with this technique--overestimate blast damage. This suggests that earlier damage estimates near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes.

Toward the most ideal case-control design with related and unrelated dogs in whole-exome sequencing studies.

With the recent development of whole-exome sequencing enrichment designs for the dog, a novel tool for disease-association studies became available. The aim of disease-association studies is to identify one or a very limited number of putative causal variants or genes from the large pool of genetic variation. To maximize the efficiency of these studies and to provide some directions of what to expect, we evaluated the effect on variant reduction for various combinations of cases and controls for both dominant and recessive types of inheritance assuming variable degrees of penetrance and detectance. In this study, variant data of 14 dogs (13 Labrador Retrievers and one Dogue de Bordeaux), obtained by whole-exome sequencing, were analyzed. In the filtering process, we found that unrelated dogs from the same breed share up to 70% of their variants, which is likely a consequence of the breeding history of the dog. For the designs tested with unrelated dogs, combining two cases and two controls gave the best result. These results were improved further by adding closely related dogs. Reduced penetrance and/or detectance has a drastic effect on the efficiency and is likely to have a profound effect on the sample size needed to elucidate the causal variant. Overall, we demonstrated that sequencing a small number of dogs results in a marked reduction of variants that are likely sufficient to pinpoint causal variants or genes.

Successful high-resolution three-dimensional electroanatomical mapping and radiofrequency catheter ablation of a posteroseptal accessory pathway in a dog using CARTO 3.

A one-year-and-seven-month-old, 28 kg, male castrated crossbreed dog was presented for supraventricular tachycardia causing recurrent episodes of anorexia and lethargy. Sotalol (2.2 mg/kg q12 h) reduced the frequency of symptomatic episodes but did not provide full relief. Three-dimensional electroanatomical mapping was performed at the Ghent University Small Animal Teaching hospital using the CARTO 3. Right atrial activation mapping identified the earliest atrial activation right posteroseptal, near the tricuspid annulus. Fast retrograde ventriculoatrial conduction during tachycardia and extrastimulus testing confirmed the presence of a concealed right posteroseptal accessory pathway. Six radiofrequency catheter ablation applications were delivered, and tachycardia remained uninducible. The dog recovered well from the procedure. Sotalol was stopped three weeks later, and no more clinical signs were noted by the owner. Repeated 24-hour electrocardiography monitoring on day one and at one, three, and 12 months after the procedure showed no recurrence of tachycardia.

Evaluation of the use of a heparin dose-response test in dogs to determine the optimal heparin dose during intravascular procedures and assessment of the in vitro heparin response in healthy dogs.

BACKGROUND: No guidelines for administering and monitoring anticoagulants intraprocedurally are currently available in dogs, despite the prevalence of procedures necessitating systemic anticoagulation with heparin. OBJECTIVES: To evaluate an activated clotting time (ACT)-based heparin dose-response (HDR) test to predict the individual required heparin dose in dogs during intravascular procedures, and to investigate both the in vitro heparin - ACT and in vitro heparin - factor anti-Xa activity (anti-Xa) relationships in dogs. METHODS: Blood was collected from eight healthy beagles undergoing a cardiac procedure and utilised to establish baseline ACT and for in vitro evaluation. Subsequently, 100 IU/kg heparin was administered intravenously (IV) and ACT was remeasured (HDR test). The required heparin dose for an ACT target response ≥300 s was calculated for each individual and ACT was remeasured after administration of this dose. For in vitro testing, a serial heparin blood dilution (0-0.5-1-2-4 international unit (IU)/mL) was prepared and ACT and anti-Xa were determined using whole blood and frozen plasma, respectively. RESULTS: The HDR test overestimated the required heparin dose in 3/7 dogs. In vitro, ACT and anti-Xa increased significantly with increasing blood heparin concentration. Heparin - ACT was nonlinear in 4/8 dogs at heparin concentrations >2 IU/mL, whereas heparin - anti-Xa remained linear throughout the tested range. CONCLUSIONS: The HDR test poorly estimated the required heparin dose in dogs. This is most likely attributed to a nonlinear heparin - ACT relationship, as observed in vitro. Anti-Xa is a promising alternative for ACT; however, unavailability as a point-of-care test and lack of in vivo target values restrict its current use.

Large-vessel involvement in ANCA-associated vasculitis: A multicenter case-control study.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) primarily affects small vessels. Large-vessel involvement (LVI) is rare. We aimed to describe the characteristics of LVI, to identify associated risk factors, and to describe its therapeutic management. METHODS: This multicenter case-control (1:2) study included patients with AAV according to the ACR/EULAR classification and LVI as defined by the Chapel Hill nomenclature, together with controls matched for age, sex, and AAV type. RESULTS: We included 26 patients, 15 (58 %) of whom were men, with a mean age of 56.0 ± 17.1 years. The patients had granulomatosis with polyangiitis (n = 20), or microscopic polyangiitis (n = 6). The affected vessels included the aorta (n = 18; 69 %) supra-aortic trunks (n = 9; 35 %), lower-limb arteries (n = 5; 19 %), mesenteric arteries (n = 5; 19 %), renal arteries (n = 4; 15 %), and upper-limb arteries (n = 2; 8 %). Imaging showed wall thickening (n = 10; 38 %), perivascular inflammation (n = 8; 31 %), aneurysms (n = 5; 19 %), and stenosis (n = 4; 15 %). Comparisons with the control group revealed that LVI was significantly associated with neurological manifestations (OR=3.23 [95 % CI: 1.11-10.01, p = 0.03]), but not with cardiovascular risk factors (OR=0.70 [95 % CI: 0.23-2.21, p = 0.60]), or AAV relapse (OR=2.01 [95 % CI: 0.70-5.88, p = 0.16]). All patients received corticosteroids, in combination with an immunosuppressant in 24 (92 %), mostly cyclophosphamide (n = 10, 38 %) or rituximab (n = 9, 35 %). CONCLUSION: Regardless of distinctions based on vessel size, clinicians should consider LVI as a potential manifestation of AAV, with the aorta commonly affected. The risk of developing LVI appears to be greater for clinical phenotypes of AAV with neurological involvement. Standard AAV treatment can be used to manage LVI.

Pulmonary arteriovenous malformation and a concurrent patent ductus arteriosus in a Doberman.

A 7-week-old male Doberman presented with tachypnea, dyspnea and a VI/VI, left cranial, continuous heart murmur. Thoracic radiographs revealed severe left-sided cardiomegaly, presence of a rounded soft tissue opacity in the caudodorsal aspect of the thoracic cavity and signs of left-sided congestive heart failure. Clinical signs of heart failure were medically controlled. Echocardiography and computed tomography demonstrated a left-to-right shunting patent ductus arteriosus (PDA) in combination with a right-to-left shunting pulmonary arteriovenous malformation (PAVM) between the right main pulmonary artery and the right caudal pulmonary vein. Arterial blood gasses revealed mild hypoxemia. Transcatheter occlusion of the PDA using an Amplatz Canine Duct Occluder was performed. Four months post-operatively, echocardiography showed normal cardiac size and function with complete PDA closure. Thoracic radiographs revealed absence of the rounded opacity and resolution of cardiomegaly and vascular congestion. The PAVM was no longer visualized on repeated computed tomography and the arterial blood gasses were within normal limits. A PAVM connecting a pulmonary artery to a pulmonary vein has only rarely been reported in dogs. This report describes the presence of a congenital PAVM in combination with a PDA in a dog, which has not been previously reported in veterinary medicine.

Three-dimensional electroanatomical mapping for guidance of pulmonary vein isolation as treatment for persistent atrial fibrillation in a dog.

A two-year and four-month, male German Shepherd was referred for exercise intolerance and panting. Irregular heart auscultation (250 beats per minute (bpm)) and pulse deficits were noted on physical exam. Electrocardiogram (ECG) showed irregular, narrow-QRS tachycardia without P waves compatible with coarse atrial fibrillation (AF). A 24-h ECG showed sustained AF (mean ventricular response rate 92 bpm). Echocardiography showed no structural abnormalities. Given the young age and presence of AF-related symptoms, rhythm control was preferred. Transthoracic electrical cardioversion was successfully performed six weeks later but AF recurred within 24-h. Sotalol was started but discontinued due to poor tolerance and AF persisted. Seven months after AF diagnosis, radiofrequency catheter ablation (RFCA) aiming for pulmonary vein isolation was performed under general anaesthesia. After transseptal puncture, three-dimensional electroanatomical mapping of the left atrium was performed. Point-by-point pulmonary vein isolation was achieved by RFCA. Seventy-eight RFCA lesions were placed in the left atrium encircling the three pulmonary vein ostia followed by electrical cardioversion. No complications occurred and the dog was discharged with amiodarone. In the immediate post-operative phase, there was recurrence of persistent AF requiring electrical cardioversion. Furthermore, at one month after the ablation, the dog experienced a single and transient paroxysm of AF. Since then, stable sinus rhythm (SR) was retained on daily ECG monitoring at home and confirmed by 24-h ECG three months post-operatively. Amiodarone was stopped subsequently. At the time of writing (one year post-operative), the dog remains in SR with normal exercise tolerance.

Surgical correction of an infundibular pulmonic stenosis and ventricular septal defect in a Shetland Sheepdog.

A four-month-old male Shetland Sheepdog presented with exercise intolerance. Physical examination revealed an IV/VI left cranial systolic heart murmur. Echocardiography showed a severe infundibular pulmonic stenosis and a concomitant restrictive ventricular septal defect. As clinical signs of congestive right-sided heart failure worsened and were refractory to medical treatment, surgical correction was advised. Via sternotomy, with cardiopulmonary bypass and cardioplegic cardiac arrest, ventricular septal defect closure and resection of the stenotic infundibular band were performed through right ventriculotomy, followed by patch enlargement. Postoperative recovery was uneventful and echocardiography showed complete resolution of the stenosis and successful closure of the ventricular septal defect. Follow-up echocardiography revealed restenosis after seven weeks and recurrence of right-sided heart failure three months postoperatively. Stenting of the restenosis was attempted via a hybrid procedure with sternotomy and direct transventricular approach. The dog developed fatal ventricular fibrillation during stent deployment. This is the first dog in which surgical right ventricular patch enlargement under cardiopulmonary bypass is reported for the treatment of a primary infundibular pulmonic stenosis.

Feasibility and safety of three-dimensional electroanatomical cardiac mapping, mapping-guided biopsy and transseptal puncture in dogs.

Three-dimensional electroanatomical mapping (3D EAM) has expanded radiofrequency catheter ablation applications in humans to almost all complex arrhythmias and has drastically reduced fluoroscopy use, yet its potential in dogs is poorly investigated. The objectives of the current study were to assess the feasibility and safety of 3D EAM of all four heart chambers, 3D EAM-guided biopsies and transseptal puncture in dogs. Eight healthy purpose-bred Beagle dogs. Electroanatomical mapping was performed under general anaesthesia during sinus rhythm using a 22-electrode mapping catheter. Left heart catheterisation was achieved by either retrograde transaortic access (n = 4) or transseptal puncture (n = 4). Successful 3D EAM of the right atrium and ventricle was achieved in all dogs at a median time of 33 (13-40) min and 17 (3-52) min, respectively. Left atrial and ventricular 3D EAM was successful in six and seven dogs, at a median time of 17 (4-27) min and 8 min (4-19 min), respectively. Complications requiring intervention occurred in one dog only and were a transient third degree atrioventricular block and pericardial effusion following transseptal puncture, which was treated by pericardiocentesis. All dogs recovered uneventfully. Fluoroscopy time was limited to a median of 7 min (0-45 min) and almost exclusively associated with transseptal puncture. Three-dimensional EAM of all cardiac chambers, including mapping-guided biopsy and transseptal puncture is feasible in small dogs. Complications are similar to those reported in human patients. This suggests a potential added value of 3D EAM to conventional electrophysiology in dogs with arrhythmias.

The predictive value of clinical, radiographic, echocardiographic variables and cardiac biomarkers for assessing risk of the onset of heart failure or cardiac death in dogs with preclinical myxomatous mitral valve disease enrolled in the DELAY study.

OBJECTIVES: To identify the predictive value on time to onset of heart failure (HF) or cardiac death of clinical, radiographic, and echocardiographic variables, as well as cardiac biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin I in dogs with preclinical myxomatous mitral valve disease (MMVD). ANIMALS: One hundred sixty-eight dogs with preclinical MMVD and left atrium to aortic root ratio ≥1.6 (LA:Ao) and normalized left ventricular end-diastolic diameter ≥1.7 were included. METHODS: Prospective, randomized, multicenter, single-blinded, placebo-controlled study. Clinical, radiographic, echocardiographic variables and plasma cardiac biomarkers concentrations were compared at different time points. Using receiving operating curves analysis, best cutoff for selected variables was identified and the risk to develop the study endpoint at six-month intervals was calculated. RESULTS: Left atrial to aortic root ratio >2.1 (hazard ratio [HR] 3.2, 95% confidence interval [95% CI] 1.9-5.6), normalized left ventricular end-diastolic diameter > 1.9 (HR: 6.3; 95% CI: 3.3-11.8), early transmitral peak velocity (E peak) > 1 m/sec (HR: 3.9; 95% CI: 2.3-6.7), and NT-proBNP > 1500 ρmol/L (HR: 5.7; 95% CI: 3.3-9.5) were associated with increased risk of HF or cardiac death. The best fit model to predict the risk to reach the endpoint was represented by the plasma NT-proBNP concentrations adjusted for LA:Ao and E peak. CONCLUSIONS: Logistic and survival models including echocardiographic variables and NT-proBNP can be used to identify dogs with preclinical MMVD at higher risk to develop HF or cardiac death.

Escherichia coli pyometra induces transient glomerular and tubular dysfunction in dogs.

BACKGROUND: Pyometra in dogs has been associated with renal injury. HYPOTHESIS: Examine pyometra-related nephropathy by evaluating novel renal biomarkers. ANIMALS: Twenty-five dogs with Escherichia coli pyometra. Fourteen clinically healthy bitches of comparable age. METHODS: Prospective study. Urinary biomarkers determined by immunoassays (uIgG, uCRP, uAlb, uRBP, uTXB2) or colorimetric test (uNAG) with results normalized to urine creatinine concentration. Nonparametric Mann-Whitney U-test and Wilcoxon's signed-rank test used to compare healthy dogs and dogs with pyometra, and dogs with pyometra at initial and follow-up examination. RESULTS: Urinary biomarkers (median, range) significantly increased in dogs with pyometra (uIgG/Cr: 169.7 mg/g, 4.8-1052.9; uCRP/Cr: 0.260 mg/g, 0.006-3.030; uAlb/Cr: 89.5 mg/g, 8.8-832.7; uRBP/Cr: 1.66 mg/g, 0.05-21.44; uNAG/Cr: 5.8 U/g, 1.6-27.7; uTXB2 /Cr: 15.3 µg/g, 3.2-139.6) compared with healthy bitches (uIgG/Cr: 3.4 mg/g, 0.6-8.9; uCRP/Cr: below detection limit; uAlb/Cr: 17.5 mg/g, 1.3-166.3; uRBP/Cr: 0.13 mg/g, 0.02-0.44; uNAG/Cr: 2.4 U/g, 1.4-7.4; uTXB2 /Cr: 2.4 µg/g, 1.2-4.7) (P<.001). Six months after ovariohysterectomy, urinary biomarkers in pyometra group (uIgG/Cr: 4.7 mg/g, 1.5-99.8; uCRP/Cr: below detection limit; uAlb/Cr: 13.9 mg/g, 2.1-471.2; uRBP/Cr: 0.05 mg/g, 0.02-0.32; uNAG/Cr: 1.6 U/g, 0.9-3.3; uTXB2 /Cr: 3.3 µg/g, 1.0-6.9) were significantly lower than before surgery (P<.01), and not significantly different to those of healthy dogs (P>.05). CONCLUSION AND CLINICAL IMPORTANCE: Pyometra-related renal dysfunction affects the nephron both at glomerular and proximal tubular level and is a transient process in most dogs with E. coli pyometra.

Urinary markers in healthy young and aged dogs and dogs with chronic kidney disease.

BACKGROUND: Blood urea nitrogen and serum creatinine concentrations only detect a decrease of > 75% of renal functional mass. Therefore, there is a need for markers that allow early detection and localization of renal damage. HYPOTHESIS: Urinary albumin (uALB), C-reactive protein (uCRP), retinol binding protein (uRBP), and N-acetyl-beta-D-glucosaminidase (uNAG) concentrations are increased in dogs with chronic kidney disease (CKD) compared with healthy controls and in healthy older dogs compared with young dogs. ANIMALS: Ten dogs with CKD, 10 healthy young dogs (age 1-3 years), and 10 healthy older dogs (age > 7 years) without clinically relevant abnormalities on physical examination, hematology, biochemistry, and urinalysis. METHODS: Urinary markers were determined using an ELISA (uALB, uCRP, and uRBP) or a colorimetric test (uNAG). Results were related to urinary creatinine (c). The fixed effects model or the Wilcoxon rank sum test were used to compare the different groups of dogs. RESULTS: uALB/c, uRBP/c, and uNAG/c were significantly higher in CKD dogs than in healthy dogs. No significant difference was found for uCRP, which was not detectable in the healthy dogs and only in 3 of the CKD dogs. Between the healthy young and older dogs, no significant difference was detected for any of the markers. CONCLUSION: The urinary markers uALB/c, uRBP/c, and uNAG/c were significantly increased in dogs with CKD compared with healthy controls. Additional studies are needed to evaluate the ability of these markers to detect renal disease before the onset of azotemia.

DELay of Appearance of sYmptoms of Canine Degenerative Mitral Valve Disease Treated with Spironolactone and Benazepril: the DELAY Study.

INTRODUCTION: Efficacy of renin-angiotensin-aldosterone system (RAAS) blockade using angiotensin-converting enzyme inhibitors (ACEi) in dogs with preclinical myxomatous mitral valve disease (MMVD) is controversial. HYPOTHESIS: Administration of spironolactone (2-4 mg q 24 h) and benazepril (0.25-0.5 mg q 24 h) in dogs with preclinical MMVD, not receiving any other cardiac medications, delays the onset of heart failure (HF) and cardiac-related death. Moreover, it reduces the progression of the disease as indicated by echocardiographic parameters and level of cardiac biomarkers N-terminal pro brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI). ANIMALS: 184 dogs with pre-clinical MMVD and left atrium-to-aortic root ratio (LA:Ao) ≥1.6 and normalized left ventricular end-diastolic diameter (LVEDDn) ≥1.7. METHODS: This is a prospective, randomized, multicenter, single-blinded, placebo-controlled study. Primary outcome variable was time-to-onset of first occurrence of HF or cardiac death. Secondary end points included effect of treatment on progression of the disease based on echocardiographic and radiographic parameters, as well as variations of NT-proBNP and cTnI concentrations. RESULTS: The median time to primary end point was 902 days (95% confidence interval (CI) 682-not available) for the treatment group and 1139 days (95% CI 732-NA) for the control group (p = 0.45). Vertebral heart score (p = 0.05), LA:Ao (p < 0.001), LVEDDn (p < 0.001), trans-mitral E peak velocity (p = 0.011), and NT-proBNP (p = 0.037) were lower at the end of study in the treatment group. CONCLUSIONS: This study failed in demonstrating that combined administration of spironolactone and benazepril delays onset of HF in dogs with preclinical MMVD. However, such treatment induces beneficial effects on cardiac remodeling and these results could be of clinical relevance.

Effect of thyroxine supplementation on glomerular filtration rate in hypothyroid dogs.

BACKGROUND: Glomerular filtration rate (GFR) is decreased in humans with hypothyroidism, but information about kidney function in dogs with hypothyroidism is lacking. HYPOTHESIS: Hypothyroidism influences GFR in dogs. The objective of this study was to assess GFR in hypothyroid dogs before implementation of thyroxine supplementation and after re-establishing euthyroidism. ANIMALS: Fourteen hypothyroid dogs without abnormalities on renal ultrasound examination or urinalysis. METHODS: Blood pressure and GFR (measured by exogenous creatinine clearance) were measured before treatment (T0, n=14) and at 1 month (T1, n=14) and at 6 months (T6, n=11) after beginning levothyroxine supplementation therapy (20 microg/kg/d, PO). The response to therapy was monitored at T1 by measuring serum total thyroxine and thyroid stimulating hormone concentrations. If needed, levothyroxine dosage was adjusted and reassessed after 1 month. Statistical analysis was performed using a general linear model. Results are expressed as mean+/-standard deviation. RESULTS: At T0, the average age of dogs in the study group was 6.3+/-1.4 years. Their average body weight decreased from 35+/-18 kg at T0 to 27+/-14 kg at T6 (P<.05). All dogs remained normotensive throughout the study. GFR increased significantly with levothyroxine supplementation; the corresponding results were 1.6+/-0.4 mL/min/kg at T0, 2.1+/-0.4 at T1, and 2.0+/-0.4 at T6 (P<.01). CONCLUSION: GFR was <2 mL/min/kg in untreated hypothyroid dogs. Re-establishment of a euthyroid state increased GFR significantly.

Retinol-binding protein in serum and urine of hyperthyroid cats before and after treatment with radioiodine.

BACKGROUND: Retinol-binding protein (RBP) is suggested as a clinically useful marker of renal function in cats. HYPOTHESIS: Serum and urinary RBP concentrations in hyperthyroid (HT) cats differ from those in healthy (H) cats; radioiodine ((131)I) treatment influences serum and urinary RBP concentrations in HT cats. ANIMALS: Ten HT and 8 H cats. METHODS: RBP concentration was evaluated in feline serum and urine samples from a prospective study. RESULTS: There was a significant (P= .003) difference in the urinary RBP/creatinine (uRBP/c) ratios of H (-) and untreated HT (1.4 + or - 1.5 x 10(-2) microg/mg) cats. Serum total thyroxine concentration (1.8 + or - 1.9 microg/dL, 24 weeks) and uRBP/c (0.6 + or - 1.0 x 10(-2) microg/mg, 24 weeks) decreased significantly (P < .001) in HT cats at all time points after treatment with (131)I, and these variables were significantly correlated with one another (r= 0.42, P= .007). Serum RBP concentrations from HT cats (199 + or - 86 microg/L) did not differ significantly (P= .98) from those of H cats (174 + or - 60) and did not change after treatment with (131)I (182 + or - 124 microg/L, P= .80). CONCLUSION AND CLINICAL IMPORTANCE: The presence of urinary RBP in HT cats is a potential marker of tubular dysfunction that is correlated to thyroid status, although it is independent of circulating RBP concentrations. The decreased uRBP/c combined with the absence of changes in serum RBP after treatment suggests that the suspected tubular dysfunction was partly reversible with treatment of (131)I.

Very painful acute frontal sinusitis revealing granulomatosis with polyangiitis.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is a necrotizing vasculitis of small and medium-sized vessels comprising inflammation of the vessel wall and perivascular and extravascular granulomas, frequently presenting in the form of chronic sinusitis. OBSERVATION: We report the case of a 27-year-old man who presented with very painful acute frontal sinusitis that was managed medically and surgically. The symptoms rapidly recurred despite treatment and CT scan demonstrated diffuse thickening of the sinus mucosa. Anti-proteinase 3 ANCA were positive. Biopsy of a pulmonary nodule confirmed the diagnosis of GPA. The patient was treated with corticosteroids in combination with rituximab, resulting in improvement of the clinical, laboratory and CT signs. DISCUSSION: In the presence of persistent, acute, localized sinusitis despite appropriate treatment, associated systemic signs and/or the presence of other signs suggestive of GPA, the ENT surgeon must request a targeted work-up. In the absence of treatment, GPA can be fatal within a few months. However, with currently available treatment, remission is obtained in 80% of cases with a 75% 10-year survival rate.

A dose-escalation study of combretastatin A4-phosphate in healthy dogs.

Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer. Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m-2 . At all 3 CA4P doses, nausea, abdominal discomfort as well as diarrhoea were observed for several hours following administration. Likewise, a low-grade neutropenia was observed in all dogs. Doses of 75 and 100 mg m-2 additionally induced vomiting and elevation of serum cardiac troponine I levels. At 100 mg m-2 , low-grade hypertension and high-grade neurotoxicity were also observed. In healthy dogs, doses up to 75 mg m-2 seem to be well tolerated. The severity of the neurotoxicity observed at 100 mg m-2 , although transient, does not invite to use this dose in canine oncology patients.

A single dose of intravenous combretastatin A4-phosphate is reasonably well tolerated and significantly reduces tumour vascularization in canine spontaneous cancers.

Combretastatin A4-phosphate (CA4P) is an anti-tumour vascular targeting agent which selectively blocks tumour blood flow. Research on CA4P in rodent tumour models is extensive; however, knowledge of its effect on spontaneous cancer is scarce. This study was conducted in canine patients with spontaneous solid tumours. The goal was to assess the toxicity and efficacy of CA4P in various spontaneous tumour types. Eight dogs with spontaneous tumours were enrolled and treated with a single dose of 75 mg m-2 intravenous CA4P. The dogs were screened and monitored before and after injection. Pre- and post-treatment tumour blood flow was analysed in vivo by power Doppler ultrasound (PDUS) and contrast-enhanced ultrasound (CEUS). Vessel destruction and tumour necrosis were evaluated by histopathology. Clinically relevant toxicity was limited to one case of temporary tetraparesis; other adverse events were mild. Significant cardiovascular changes were mostly confined to changes in heart rate and cTnI levels. Macroscopic tumour size reduction was evident in 2 dogs. Based on PDUS and CEUS, CA4P induced a significant decrease in vascular index and tumour blood flow. Post-treatment, histopathology revealed a significant increase of necrotic tumoural tissue and a significant reduction in microvessel density in tumoural tissue. Anti-vascular and necrotizing effects of CA4P were documented in a variety of canine spontaneous cancers with only minimal side effects. This is the first study reporting the administration of CA4P to canine cancer patients with in vivo and ex vivo assessment, and a first step toward implementing CA4P in combination therapies in veterinary oncology patients. The use of CA4P in canine patients was approved and registered by the Belgian Federal Agency for Medicines and Health Products (FAMHP) (approval number 0002588, registration number 6518 ID 2F12).

Combretastatin A4-phosphate and its potential in veterinary oncology: a review.

For many years, research on anticancer therapy has focussed almost exclusively on targeting cancer cells directly, to selectively kill them or restrict their growth. But limited advances in this strategy have led researchers to shift their attention to other potential targets. Active research is now on-going on targeting tumour stroma. Vascular disrupting agents (VDAs) appear a promising class of anticancer drugs that are currently under investigation as a sole or combined therapy in human cancer patients. This article will briefly touch on the history and biology of combretastatin A4-phosphate (CA4P) as a typical example of VDAs and will concentrate on the side effects that can be expected when used in veterinary patients. Particularly, the pathogenesis of these side effects and how they may be prevented and/or treated will be discussed. The purpose of this article is to illustrate the potentials of CA4P as anticancer therapy in veterinary oncology patients.